The purpose of this project is to build an interdisciplinary, multi-institutional, collaborative group to create analytical, mathematical models of nucleocytoplasmic transport in the living cell. Nuclear transport is a process of fundamental importance to eukaryotic cells. Most forms of nuclear transport are mediated by soluble carriers that recognize targeting signals in their cargo. Assembly of carrier/cargo complexes for import are dissociated in the nucleus by the small GTPase, Ran. Assembly of export complexes requires Ran-GTP, and dissociation in the cytoplasm is triggered by Ran-GTP hydrolysis. Ran itself is carried into the nucleus by a factor called NTF2. Transport occurs through pores in the nuclear envelope. Numerous viruses, including HIV, subvert nuclear transport pathways to insert their genomes into the nucleus and to ensure that viral RNAs are preferentially exported to the cytoplasm. Although a wealth of information has been accumulated on the molecular details of transport, there is little or no understanding of how nuclear transport is controlled at a global level, and of how distinct transport pathways are integrated. The proposed collaboration involves two laboratories at the University of Virginia, working on nucleocytoplasmic transport in mammalian cells (Macara) and budding yeast (Pemberton), and a group that is developing a server-based modeling environment called the Virtual Cell, at the University of Connecticut (Loew). Preliminary studies on a model for Ran import have established the value of this collaborative effort. The proposal offers a unique opportunity to employ the combined expertise of cell biologists, yeast geneticists, computer scientists, physicists and mathematicians to raise our understanding of nuclear transport.